Defining the mechanisms that initiate and promote perpetuation of rheumatic and autoimmune diseases is a compelling goal within the fields of immunology, genetics, and medicine. The important contributors to disease clearly include genetic factors, environmental triggers, and stochastic or chance events that are played out through altered function of lymphocytes and inflammatory cells. Extensive efforts to uncover disease genes have met with frustration, in spite of abundant data that identify genomic loci that are statistically associated with disease. A pilot analysis of lupus susceptibility loci, along with regions of the genome negative for putative rheumatic disease genes, demonstrated the frequent presence of full-length genomic elements, some of which are polymorphic, near microsatellite markers associated with disease. Some of these repeat elements, termed long interspersed nuclear elements (LINEs; L1), are located within intronic segments of host genes, including some that have previously been associated with the pathogenesis of complex diseases. These preliminary data stimulated elaboration of the following hypothesis: the presence of polymorphic full-length copies of L1 elements identifies candidate disease genes and may contribute to disease by modifying expression, function, or immunogenicity of those host genes. The proposed research will advance this novel concept by identifying the genes associated with full-length L1 elements throughout the human genome and by testing the prevalence of several polymorphic full-length L1 elements associated with immune system genes in patients with systemic autoimmune disease and control subjects. The specific aims are 1) to identify the human genes harboring full-length L1 elements, and 2) to assess the prevalence of polymorphic full-length L1 elements in the CD38 and BRD7 genes among rheumatic disease patients and controls. While high risk, investigation of this innovative concept may have an important impact on defining the genetic contributions to rheumatic diseases, with additional diagnostic and therapeutic implications for all complex diseases.